Summary Basis of Decision for Imaavy

Clinical Pharmacology

Nipocalimab, the medicinal ingredient in Imaavy, is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that binds to the neonatal Fc receptor (FcRn) with high specificity and affinity at both neutral (extracellular) and acidic (intracellular) pH, thereby blocking the binding of IgG and thus increasing its degradation rate. This results in a decrease in circulating IgG antibody concentrations.

The clinical pharmacology program for nipocalimab comprised 13 studies (nine Phase I, two Phase II, one Phase III, and one Phase II/III) and 5 modelling reports. These data support the recommended dosing regimen for Imaavy: an initial dose of 30 mg/kg administered as an intravenous infusion over approximately 30 minutes, followed 2 weeks later by a maintenance dose of 15 mg/kg administered as an intravenous infusion over approximately 15 minutes every 2 weeks.

Nipocalimab demonstrates non-linear, dose-dependent pharmacokinetics. Population pharmacokinetic analyses indicated no clinically significant impact on nipocalimab exposure based on age, sex, race, and mild or moderate renal or hepatic impairment; therefore, dose adjustment is not required. Pharmacodynamic assessments demonstrated reductions in total IgG (by approximately 69% of the median pre-dose level) by Week 2, with similar decreases in anti-acetylcholine receptor (AChR) and anti-muscle-specific tyrosine kinase (MuSK) autoantibodies.

Due to the mechanism of action of nipocalimab, concomitant therapies that bind FcRn (e.g., IgG products, IgG-based monoclonal antibodies, and Fc fusion proteins) may exhibit reduced exposure. This risk is addressed in the Product Monograph for Imaavy.

Pharmacokinetic exposures and IgG reductions in adolescents aged 12 years to under 18 years were comparable to those observed in adults.

For further details, please refer to the Product Monograph for Imaavy, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Imaavy as an add-on to standard therapy for the treatment of generalized myasthenia gravis in adult patients who are autoantibody (anti-AChR and anti-MuSK) positive was demonstrated in Study-011, a randomized, multicentre, placebo-controlled study that comprised a completed 24-week double-blind phase and an ongoing open-label extension phase. During the double-blind phase, 196 patients were randomized 1:1 to receive Imaavy at a loading dose of 30 mg/kg via intravenous infusion, followed by a maintenance dose of 15 mg/kg via intravenous infusion every two weeks (98 patients), or placebo infusions every 2 weeks (98 patients), added to standard therapy in both groups. There were 153 antibody-positive patients; 88% were positive for anti-AChR antibodies and 10% were positive for anti-MuSK antibodies. Baseline characteristics of patients were similar between treatment groups. Patients had a median age of 52 years at screening (range: 20 to 81 years) and a median time since diagnosis of 6 years. The majority of patients (60.1%) were female, 62.7% were White, 32.0% were Asian, 1.3% were Black or African American, 0.7% were American Indian or Alaskan Native, and for 3.3% of patients the race/ethnicity had not been reported. At baseline, the median Myasthenia Gravis Activities of Daily Living (MG-ADL) total score (ranging from 0 to 24), which assesses the impact of generalized myasthenia gravis on eight daily function items, was 9, and the median Quantitative Myasthenia Gravis (QMG) total score (ranging from 0 to 39), a 13-item standardized examination that assesses muscle weakness, was 15. At baseline, over 97% in each treatment group were on stable background standard of care therapy. In the Imaavy group, 83% were on acetylcholinesterase inhibitors (AChE) inhibitors, 61% were on steroids, and 53% were on non-steroidal immunosuppressive therapies (NSISTs) at stable doses. In the placebo group, 87% were on AChE inhibitors, 71% were on steroids, and 54% were on NSISTs at stable doses.

The primary efficacy endpoint was the mean change from baseline in MG-ADL total score over weeks 22, 23, and 24. Key secondary endpoints included the mean change from baseline in the QMG total score over weeks 22 and 24, and the proportion of MG-ADL clinical responders, defined as patients with an improvement of at least 2 points from baseline averaged over weeks 22, 23, and 24.

Study results showed a statistically significant improvement in the change from baseline in MG-ADL total score and QMG total score in the Imaavy group compared with the placebo group at Week 24, with a mean difference in MG-ADL total score of -1.45 (95% confidence interval [CI]: -2.38, -0.52; p = 0.003) and a mean difference in QMG total score of -2.81 (95% CI: -4.11, -1.41; p = 0.001). The proportion of MG-ADL responders also supported the results of the primary efficacy analysis (68.8% in the Imaavy group versus [vs.] 52.6% in the placebo group; p = 0.02). Among seropositive patients, changes in the MG-ADL total scores were consistent across the anti-AChR and anti-MuSK antibody-positive subgroups. In addition, treatment with Imaavy resulted in a 68% reduction in serum IgG levels, a 65% reduction in anti-AChR antibody levels, and a 38% reduction in anti-MuSK antibody levels from baseline at Week 24.

The scientific evidence regarding the tolerability, efficacy, and safety of Imaavy when administered as an add-on to standard therapy to adolescent patients 12 years of age and older with generalized myasthenia gravis and who are anti-AChR antibody positive was obtained from 7 patients from Cohort 1 of the 24-week pediatric Phase II/III Study-2001. Imaavy was administered according to the treatment regimen used in the pivotal Study-011. In Study-2001, treatment with Imaavy resulted in a 70% reduction in serum IgG levels and a 47% reduction in the anti-AChR antibody levels from baseline at Week 24. This was consistent with the results seen in adult patients with generalized myasthenia gravis. Although limited, the data for Imaavy as an add-on to standard therapy in adolescent patients with generalized myasthenia gravis, when considered along with the similarity of the disease pathophysiology in adolescent and adult populations, allow for the extrapolation of the efficacy and safety data provided from adult patients to adolescent patients 12 years of age and older. Such an extrapolation supported the authorization of an indication of Imaavy as an add-on to standard therapy for the treatment of generalized myasthenia gravis in pediatric patients 12 years of age and older who are anti-AChR or anti-MuSK antibody positive.

Indication

The New Drug Submission for Imaavy was filed by the sponsor with the following proposed indication:

Imaavy (nipocalimab) is indicated for the treatment of generalized myasthenia gravis (gMG) in adults (≥18 years) and adolescent patients (12 to <18 years) who are antibody positive (anti-acetylcholine receptor [AChR], anti-muscle-specific tyrosine kinase [MuSK], or anti-low-density lipoprotein receptor-related protein 4 [LRP4]).

To support safe and effective use of the product, Health Canada approved the following indication:

Imaavy (nipocalimab) is indicated as an add-on to standard therapy for the treatment of generalized myasthenia gravis (gMG) in adult and adolescent patients aged 12 years and older who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive.

For more information, refer to the Product Monograph for Imaavy, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Imaavy as an add-on to standard therapy for the treatment of generalized myasthenia gravis was demonstrated in Study-011, described in the Clinical Efficacy section. In total, 196 adult patients with generalized myasthenia gravis were exposed to at least one dose of Imaavy and 140 of those patients had at least 12 months of exposure to Imaavy at the recommended dose.

The most common adverse events (occurring in 5% or more of patients) reported more frequently in the Imaavy group than in the placebo group during the double-blind phase were respiratory tract infection (18.4% vs. 13.3%), urinary tract infection (6.1% vs. 3.1%), peripheral edema (12.2% vs. 2.0%), and muscle spasms (12.2% vs. 3.1%). While no deaths were reported in the double-blind phase of the pivotal study, five deaths were reported in the open‑label extension phase (no control arm). None of these deaths were however considered related to treatment with Imaavy. Serious adverse events in Imaavy-treated patients included infections (pneumonia and herpes zoster oticus), worsening myasthenia gravis or myasthenic crisis, and venous thromboembolism (pulmonary embolism).

Increases from normal to high levels of fasting total cholesterol and low-density lipoprotein (LDL) cholesterol occurred in 24% and 11% of Imaavy-treated patients and in 2% and 5% of placebo-treated patients, respectively. Decreases from normal to low levels of high-density lipoprotein (HDL) were reported in 5% of Imaavy-treated patients compared with 3% of placebo-treated patients. Increases in cholesterol levels did not lead to study discontinuation in any patients.

Based on the limited safety data from Study-2001 in adolescent patients with generalized myasthenia gravis (7 patients), the adverse events observed in this population were generally consistent with those reported in adults with generalized myasthenia gravis in Study-011. Accordingly, the anticipated safety profile of Imaavy is not expected to be different in pediatric patients 12 years of age and older, regardless of whether they are anti-AChR or anti-MuSK antibody positive.

Overall, the benefit-risk profile of Imaavy as an add-on to standard therapy for the treatment of generalized myasthenia gravis is favourable in adult and adolescent patients aged 12 years and older with generalized myasthenia gravis and who are AChR or anti-MuSK antibody positive.

Appropriate warnings and precautions are in place in the approved Product Monograph for Imaavy to address the identified safety concerns.

For more information, refer to the Product Monograph for Imaavy, approved by Health Canada and available through the Drug Product Database.

Nipocalimab is the medicinal ingredient in Imaavy. The mechanism of action of nipocalimab, i.e., its ability to bind the neonatal Fc receptor (FcRn) with sufficient affinity and thereby reduce serum immunoglobulin G (IgG) levels, was adequately demonstrated by in vitro and in vivo pharmacodynamic studies. Cynomolgus monkeys were administered nipocalimab by intravenous infusion once weekly for 26 weeks at doses that produced nipocalimab exposures equal to 0.4 to 44 times the human exposure at the recommended maintenance dose, based on the area under the concentration-time curve (AUC). Some animals administered nipocalimab developed skin lesions (at the tip of the tail) and/or other clinical signs. One male who received a high dose of nipocalimab was euthanized due to the worsening of an underlying pre-existing systemic infection that may have been exacerbated by nipocalimab-mediated suppression of total IgG. A no-observed-adverse-effect level (NOAEL) could not be determined for this study.

In an enhanced pre- and postnatal developmental study, pregnant cynomolgus monkeys were administered nipocalimab from the second trimester until parturition. The doses tested in monkeys achieved exposures that were up to 44-times the human exposure at the recommended maintenance dose, based on the AUC. In the pregnant monkeys administered nipocalimab, 4 of 25 placentas showed large, central placental infarctions. Of these 4 pregnancies, 3 were associated with fetal death or stillbirth. A NOAEL could not be determined for maternal and developmental toxicity. No non-clinical studies have been conducted to assess the potential direct or indirect effects of nipocalimab on early development and on organogenesis during the first trimester of pregnancy.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Imaavy. In view of the intended use of Imaavy, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Product Monograph for Imaavy, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

Nipocalimab, the medicinal ingredient in Imaavy, is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that binds to the neonatal Fc receptor (FcRn) with high specificity and affinity at both neutral (extracellular) and acidic (intracellular) pH, thereby blocking the binding of IgG and thus increasing its degradation rate. This results in a decrease in circulating IgG antibody concentrations. Nipocalimab has an engineered mutation that results in an aglycosylated structure that lacks Fc effector functions.

Detailed characterization studies were performed to provide assurance that nipocalimab consistently exhibits the desired characteristic structure and biological activity.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable. A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The nipocalimab drug substance is manufactured using recombinant deoxyribonucleic acid (DNA) technology in Chinese hamster ovary cells. The manufacturing process begins with fed-batch fermentation in single-use bioreactors. Next, nipocalimab is purified from the clarified harvest using protein A, cation-exchange, and mixed-mode anion-exchange chromatography. Any present viruses are inactivated and removed using solvent/detergent inactivation and viral filtration. Ultrafiltration/diafiltration and tangential flow filtration are used to facilitate protein concentration and buffer exchange prior to formulation, filtration, filling into bottles, and storage at -70 ± 10 °C to -40 ± 10 °C.

The drug product is supplied as two presentations at a concentration of 185 mg/mL nipocalimab: a single-use glass vial containing 300 mg of nipocalimab in 1.62 mL of solution and a single-use glass vial containing 1,200 mg of nipocalimab in 6.5 mL of solution. The two presentations are manufactured using the same process on the same fill line and differ only with respect to container closure and fill volume. The manufacturing process consists of drug substance thawing and dilution, sterile filtration, aseptic filling into vials, stoppering, capping, and 100% visual inspection prior to storage at 2 °C to 8 °C. Both vial sizes may be filled from the same bulk drug product batch. None of the non-medicinal ingredients (excipients) in Imaavy are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits. The sponsor has demonstrated that the manufacturing processes are capable of consistently manufacturing drug substance and drug product of acceptable quality.

Control of the Drug Substance and Drug Product

The drug substance and drug product manufacturing processes are controlled by process parameters, in-process controls, and tests that have defined operating targets/ranges, acceptance criteria, and action limits. The criticality of the process parameters and in-process controls were based on the outcome of product quality attribute assessments, risk assessments, and process characterization studies.

The in-process and specification acceptance criteria were suitably justified and ensure the safety, identity, strength, potency, and purity of the drug substance and drug product. The in-house analytical methods were validated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines and the compendial methods complied with pharmacopeia standards. A two-tiered reference standard program has been established, which consists of primary and working reference standards. Overall, the control strategy ensures suitable drug substance and drug product quality over the product lifetime.

Imaavy is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24-month shelf life is acceptable when Imaavy is stored at 2 °C to 8 °C and protected from light.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of all facilities and equipment involved in the production are considered suitable.

Taking into consideration the positive outcome of a recent virtual site evaluation performed by Health Canada, an on-site evaluation of the drug substance manufacturing facility was not recommended. Furthermore, based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug product manufacturing facility was not deemed necessary.

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure absence of adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

Raw materials of animal and recombinant DNA origin used in the manufacturing process are adequately tested to ensure absence of adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.